Sulfonamide compositions

ABSTRACT

Aqueous parenteral solutions of from about 10 to 20% w/v of sulfamethoxazole or sulfadoxine and about 3 to 5% w/v of trimethoprim in from 60 to 80% w/v of 2-pyrrolidone are disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of copending application Ser. No.54,546, filed July 5, 1979, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to sulfonamide solutions suitable forpharmaceutical use. More particularly, it relates to aqueous parenteralsolutions of sulfamethoxazole or sulfadoxine with trimethoprim in2-pyrrolidone.

Antibacterial compositions containing sulfamethoxazole and trimethoprimare disclosed in U.S. Pat. No. 3,515,783.

Parenteral solutions of sulfamethoxazole and trimethoprim containing thefollowing water-miscible solvents are disclosed in U.S. Pat. No.3,551,564: polyethyleneglycol ethers of tetrahydrofurfuryl alcohol,dimethylformamide, dimethylsulfoxide, dimethylacetamide,diethylacetamide, 1,2-propyleneglycol, di-(1,2-propyleneglycol),1,3-butylene glycol, glycerol formal, diethylene glycol and polyethyleneglycol containing 2-15 ethylene oxide groups.

U.S. Pat. No. 3,985,876 discloses solutions of trimethoprim with varioussulfonamides, including sulfamethoxazole and sulfadoxine in a mixture of10-60% water and 30-90% organic solvents such as dimethyl anddiethylacetamide, dimethyl formamide, dimethylsulfoxide, glycerol formaland various glycols.

U.S. Pat. No. 4,018,889 discloses oxytetracycline solutions containingfrom about 1 to 40% oxytetracycline in an aqueous vehicle containingfrom about 10 to 50% by weight of 2-pyrrolidone, about 0.8 to 1.3 molarproportions of a pharmaceutically acceptable magnesium compound solublein the said solution, said solution having a pH value in the range offrom about 7.5 to 9.5.

SUMMARY OF THE INVENTION

In accordance with this invention there is disclosed an aqueousparenteral solution of sulfamethoxazole or sulfadoxine and trimethoprimin 2-pyrrolidone.

This invention further discloses a liquid sulfonamide compositioncomprising an aqueous solution of from about 10 to 20% w/v ofsulfamethoxazole or sulfadoxine, about 3 to 5% w/v of trimethoprim infrom about 60 to 80% w/v of 2-pyrrolidone, said composition having a pHof from about 5 to 9.5.

DETAILED DESCRIPTION OF THE INVENTION

The sulfonamides utilized in the compositions of this invention aresulfamethoxazole and sulfadoxine. They are present in concentrations offrom about 10 to 20% w/v. The preferred concentration is about 20% w/v.

Sulfamethoxazole [N¹ -(5-methyl-3-isoxazolyl)sulfonilamide] isparticularly described in U.S. Pat. No. 2,888,455.

Sulfadoxine [N'-(5,6-dimethoxy-4-pyrimidyl)sulfonilamide] is describedin U.S. Pat. No. 3,132,139.

Trimethoprim is also utilized in the compositions of this invention as apotentiator in concentrations of from about 3 to 5% w/v. The preferredconcentration is about 4% w/v.

Trimethoprim [2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine] isdescribed in U.S. Pat. No. 2,909,522.

2-Pyrrolidone is present as a co-solvent for the sulfonamide andtrimethoprim in a concentration of from about 60 to 80% w/v.

2-Pyrrolidone is also known as 2-pyrrolidinone, 2-oxopyrrolidine,alpha-pyrrolidone and 2-ketopyrrolidine. It has an oral LD₅₀ of 8 gm/kgin rats and 3.8 gm/kg by intraperitoneal injection in mice.

The pH value of these compositions is adjusted if necessary to pH 5 to9.5. The pH can be adjusted by means of a base that is pharmaceuticallyacceptable, such as monoethanolamine.

As an optional ingredient polyvinylpyrrolidone having a molecular weightof between about 5,000 and 100,000 (K-12 to 30) may also be present inthese compositions in a concentration of from about 1 to 5% w/v. Thepolyvinylpyrrolidone preferred for this invention is one having anaverage molecular weight of about 10,000-17,000 (where K-value=17). Itis present in part as a cosolubilizer and may improve tissue toleration.

As optional consolvents ingredients such as propylene glycol,polyethylene glycols, benzyl alcohol, dimethylacetamide, ethyl lactateand glycerol formal may be present at concentrations of from about 0.5to 30% w/v.

The stability of these solutions for therapeutic administration is stillfurther enhanced by use of an antioxidant such as monothioglycerol atlevels of from about 0.1 to 1% w/v.

The primary application of these sulfonamide compositions is as aparenteral composition but the new compositions can also be used fortopical application.

These solutions produce efficacious blood levels and are well toleratedin contrast to the short term blood levels and tissue damage routinelyexperienced with presently available highly alkaline aqueous sulfonamidesolutions.

The sulfonamide antibiotic compositions of this invention are also easyto syringe over a wide temperature range and are satisfactory from aphysical and chemical stability standpoint. The compositions of thisinvention are preferably prepared by mixing the 2-pyrrolidone with waterand other cosolvents, if present. The sulfonamide and trimethoprim arethen added and stirred until a clear solution results. The pH is thenadjusted to the desired range. If polyvinylpyrrolidone is to beincluded, it is added to the water at the time of mixing the2-pyrrolidone.

The present invention is illustrated by the following examples. However,it should be understood that the invention is not limited to thespecific details of the examples.

EXAMPLES 1-3

    ______________________________________                                                     gm/100 ml                                                                     Example Example   Example                                                     1       2         3                                              ______________________________________                                        Sulfamethoxazole                                                                             20.00     20.00     20.00                                      Timethoprim    4.00      4.00      4.00                                       2-Pyrrolidone  60.00     60.00     70.00                                      Dimethylacetamide                                                                            --        --        10.00                                      Polyvinylpyrrolidone                                                          (K = 17)       5.00      5.00      --                                         Glycerol formal                                                                              --        20.00     --                                         Benzyl alcohol 0.90      0.90      0.90                                       Monothioglycerol                                                                             0.20      0.20      0.20                                       Monoethanolamine                                                                             4.50      4.50      --                                         Water q.s. to  100.00    100.00    100.00                                     pH             8.8       8.8       7.0                                        Viscosity cts at 25° C.                                                               35        31        28                                         ______________________________________                                    

The above solutions were prepared by dissolving all the ingredients inwater, with the sulfamethoxazole and trimethoprim being added last.

Raising the pH of Examples 1 and 2 with monoethanolamine to pH 9.5 and8.8 respectively produced similar solutions with no significantviscosity changes.

EXAMPLES 4-5

    ______________________________________                                                         gm/100 ml                                                                     Example 4                                                                             Example 5                                            ______________________________________                                        Sulfadoxine        20.00     20.00                                            Trimethoprim       4.00      4.00                                             2-Prrolidone       60.00     70.00                                            Polyvinylpyrrolidone (K = 17)                                                                    5.00      5.00                                             Dimethylacetamide  10.00     10.00                                            Glycerol formal    7.50      7.50                                             Benzyl alcohol     0.90      0.90                                             Monothioglycerol   0.20      0.20                                             Monoethanolamine   2.00      --                                               Water q.s. to      100.00    100.00                                           pH                 8.7       7.7                                              Viscosity cts at 25° C.                                                                   49        53                                               ______________________________________                                    

The above solutions were prepared by dissolving all the ingredients inwater, with the sulfadoxine and trimethoprim being added last.

EXAMPLES 6-8

    ______________________________________                                                        gm/100 ml                                                                     Example                                                                              Example  Example                                                       6      7        8                                             ______________________________________                                        Sulfadoxine       20.00    20.00    20.00                                     Trimethoprim      4.00     4.00     4.00                                      2-Pyrrolidone     80.00    80.00    70.00                                     Polyvinylpyrrolidone (K = 17)                                                                   5.00     --       --                                        Dimethylacetamide 10.00    10.00    10.00                                     Benzyl alcohol    0.90     0.90     0.90                                      Monothioglycerol  0.20     0.20     0.20                                      Monoethanolamine  --       --       2.00                                      Water q.s. to     100.00   100.00   100.00                                    pH                7.9      8.0      8.4                                       Viscosity cts at 25° C.                                                                  63       28       26                                        ______________________________________                                    

The above solutions were prepared by dissolving all the ingredients inwater, with the sulfadoxine and trimethoprim being added last.

I claim:
 1. A liquid sulfonamide composition comprising an aqueoussolution of from about 10 to 20% w/v of sulfamethoxazole and about 3 to5% w/v of trimethoprim in from about 60 to 80% w/v of 2-pyrrolidone,said composition having a pH of from about 5 to 9.5.
 2. A composition asclaimed in claim 1 wherein polyvinylpyrrolidone is also present in aconcentration of from about 1 to 5% w/v.
 3. A sulfonamide compositioncomprising an aqueous solution of about 20% w/v sulfamethoxazole, about4% w/v trimethoprim, from about 60 to 80% w/v 2-pyrrolidone and fromabout 1 to 5% w/v of polyvinylpyrrolidone, said composition having a pHvalue in the range of from about 7 to 9.5.